Rift Valley fever (RVF) is a viral zoonosis that most commonly causes disease in animals, but also can cause severe human disease. The virus is a member of the family Bunyaviridae, genus Phlebovirus and has been designated a Category A agent. The virus is most common in the Rift Valley of East Africa, especially Kenya, Somalia and Tanzania, but also has now spread outside the African continent to Saudi Arabia and Yemen. Experts have raised concerns that this infection threatens to spread further geographically. Very little is understood about human immunity to RVF. Vaccine candidates are being tested. One is an inactivated vaccine principally developed by the U.S. Army. The Army has developed and tested an improved version of inactivated RVF vaccine, designated TSI-GSD-200. At-risk workers at the US Army Medical Research Institute of Infectious Diseases (USAMRIID) were vaccinated as part of an occupational safety and health program. The second involves intramuscular (IM) injection of live-attenuated, mutagenized RVF 12th mutagenesis passage (MP-12) vaccine, which has progressed to Phase II trials, also being studied by USAMRIID. The central hypothesis of this study is that survivors of Rift Valley fever (RVF) virus infections likely possess circulating B cells encoding naturally-occurring human antibodies (Abs) that neutralize virus and protect against disease. The key requirements for successful treatment of RVF infections with monoclonal antibodies (mAbs) may include (A) use of high-affinity mAbs, and (B) administration of a cocktail of mAbs binding to the diverse viral epitopes, rather than an individual mAb. This possibility will be tested by generation of comprehensive reagents for study of RVF recognition by human Abs that will be used to define the determinants of neutralization of RVF. This proposal incorporates experts in molecular immunology and RVF virology and viral pathogenesis with access to CDC/USDA approved BSL-3 enhanced (BSL3+) facilities. We have access to blood of survivors of RVF from East Africa. In addition, we have access to blood from research subjects who were previously inoculated with inactivated or MP-12 vaccine. The proposed research is significant because it will result in generation of large panels of human mAbs that neutralize RVF, and can be used as therapeutic Abs, and the molecular, genetic, and structural basis for development of neutralizing mAbs made by survivors or vaccinees. Understanding the principles underlying molecular recognition of RVF will have a broad impact on the rational design of therapeutic Abs and development and testing of vaccines against RVF and other emerging and biothreat viruses.